The present invention relates to an electricity-assisted delivery system for transporting active agents across a body surface of a mammal (e.g., the skin or mucosa of a human). This system delivers active agents more efficiently than prior electrotransport systems.
Transdermal and topical dosage forms have been widely prescribed for decades in the treatment of systemic diseases and local conditions such as those involved with the skin and underlying tissues. Electricity may be employed to facilitate drug transport across the skin barrier. In electricity-assisted transdermal drug delivery, an electric potential (voltage) is applied to the skin to facilitate drug transport. There are three primary types of electricity-assisted drug transport through the skin barrier: iontophoresis, electro-osmosis and electroporation. In transdermal iontophoresis, an ionized drug migrates into the skin driven by an applied electric potential gradient. In electro-osmosis, a non-ionic drug to be delivered is carried by a fluid, which is driven across the skin by an applied electric potential gradient. Electroporation is the microscopic perforation of the skin barrier by extremely short pulses of high electric voltage and low electric current. These methods are described in a recent review by Sun, xe2x80x9cSkin Absorption Enhancement by Physical Means: Heat, Ultrasound, and Electricityxe2x80x9d, Transdermal and Topical Drug Delivery Systems, Ghosh, et al. Ed. Interpharm Press, Inc., 1997, pages 327-355, and Roberts, et al., xe2x80x9cSolute Structure as a Determinant of Iontophoretic Transportxe2x80x9d, Mechanisms of Transdermal Drug Delivery, Potts, et al. Ed. Marcel Dekker, 1997, pages 291-349.
In practice, there is often more than one type of the electricity-assisted drug delivery methods being employed with one drug delivery system. For example, an electrotransport system may actually deliver the active agent simultaneously with both iontophoresis and electro-osmosis. Similarly, electroporation can be used first to increase the skin permeability, followed by iontophoresis to transport the active agent through the skin barrier. In most of the cases there are little differences among the three types of electricity-assisted delivery methods in the construction of the apparatus (e.g., the drug reservoir, conductive electrode, and a counter electrode), except for the electric current supply unit.
In one aspect, the present invention relates to an apparatus for the delivery of an active agent through a body surface of a mammal (e.g., a human) comprising: (a) a housing with a delivery orifice through the housing; (b) a reservoir within the housing for containing the active agent (e.g., an ionic drug) within a fluid (e.g., a low electrolyte aqueous solution such as distilled water) where the reservoir is in communication with the delivery orifice; (c) an electrode within the reservoir where the electrode is capable of being in electronic communication with a current supply unit; and (d) a sensor within the reservoir where the sensor is capable of being in electronic communication with the current supply unit; wherein the current supply unit can modify an electric parameter at the electrode based upon feedback from the sensor. In one embodiment, the electric parameter is selected from the group consisting of current intensity, current mode, current waveform, voltage, and polarity.
The sensor measures compositional or electrical changes in the reservoir. Examples of such sensors include sensors that measure pH, conductivity, impedance, the active agent, ions, and biological compounds. In another embodiment, the apparatus comprises more than one sensor within the reservoir.
In another embodiment, the reservoir comprises: an active agent reservoir within the housing for containing the active agent where the active agent reservoir is in communication with the delivery orifice; a fluid reservoir within the housing for containing a fluid; and a semi-permeable membrane in communication with the active agent reservoir and the fluid reservoir. The semi-permeable membrane is capable of both permitting the movement of fluid (e.g., water and non-active agents solubilized therein) between the active agent reservoir and the fluid reservoir and substantially preventing the movement of the active agent between the active agent reservoir and the fluid reservoir (e.g., preventing about 75% to about 100%, such as from about 95% to about 100%, of the initial amount of active agent from leaving the active agent reservoir and entering the fluid reservoir). In one embodiment, the volume of the active agent reservoir is smaller than the volume of the fluid reservoir (e.g., at least about five times larger or at least about ten times larger). In another embodiment, the fluid reservoir comprises additional semi-permeable membranes.
In another embodiment, the housing further comprises an inlet (e.g., a septum for receiving a needle) to allow fluid to enter the reservoir (e.g., the insertion of electrode medium into the fluid reservoir or the insertion of the active agent into the active agent reservoir). In another embodiment, the reservoir comprises the active agent (e.g., a lyophilized drug).
In another embodiment, the apparatus further comprises protrusions (e.g., needles or straight-tipped or curved-tipped blades) proximate to the delivery orifice where the protrusions are capable of piercing the stratum corneum of the mammal. In a further embodiment, the protrusions are capable of piercing the stratum corneum, but are not capable of substantially piercing the dermis.
In another aspect, the invention features a system for the delivery of an active agent through the body surface of a mammal comprising: a current supply unit; a first apparatus where the first apparatus comprises: (a) a first housing with a first delivery orifice, (b) a first reservoir within the first housing for containing the first active agent where the first reservoir is in communication with the first delivery orifice, (c) a first electrode within the first reservoir where the first electrode is in electronic communication with the current supply unit; and (d) a first sensor within the first reservoir where the first sensor is in electronic communication with the current supply unit; and a second electrode in electronic communication with the current supply unit; wherein the current supply unit can modify an electric parameter (e.g., electric parameters such as polarity, current intensity and current mode or waveforms) at the first electrode based upon feedback from the first sensor. The current supply unit provides the electric voltage/potential (e.g., it can reverse the polarity) as well as the electric current needed for the electrotransport (e.g., iontophoresis, electro-osmosis, and electroporation delivery) of the active agent from the reservoir, through the orifice, and into the mammal""s body though the mammal""s body surface. The current supply unit may connected to an external current source or comprise a battery.
In one embodiment, the system further comprises a second apparatus where the second apparatus comprises a second housing with a second delivery orifice and a second reservoir within the second housing containing the second electrode where the second reservoir is in communication with the second delivery orifice. In a further embodiment, the second apparatus further comprises a second sensor within the second reservoir where the second sensor is capable of being in electronic communication with the current supply unit and where the current supply unit can modify an electric parameter at the second electrode based upon feedback from the second sensor. In another embodiment, the system comprises three or more electrodes (e.g., between three and ten electrodes) in electronic communication with the current supply unit.
In another embodiment, the current supply unit may reverse the polarity at the first electrode. The length of the interval for each polarity reversal controlled by the current supply unit is based on the feedback signals (e.g., the pH or conductivity of the fluid in the fluid reservoir) relayed from the sensor(s). The relayed signals from the sensor(s) may also assist the current supply unit to modify the current mode and current intensity from the current supply unit to the electrodes in order to achieve the desired delivery rate.
In another aspect the invention features a method for delivering an active agent through a body surface of a mammal, the method comprising the steps of: affixing the orifice of the above mentioned apparatus to a body surface of the mammal (e.g., on the skin of a human); and connecting the electrode and the sensor to a current supply unit; wherein the current supply unit supplies current to the electrode and the current supply unit can modify an electric parameter at the electrode based upon feedback from the sensor.
In still another aspect, the invention features a method for delivering an active agent through a body surface of a mammal (e.g., the skin of a human), the method comprising the steps of: affixing the first orifice of the above mentioned system proximate to the body surface of the mammal; attaching the second electrode of the above mentioned system proximate to the body surface of the mammal (e.g., proximate to the first orifice) such that current passes from the first electrode to the second electrode through the body of the mammal; wherein the current supply unit supplies current to the electrode and the current supply unit can modify an electric parameter at the electrode based upon feedback from the sensor.
Other features and advantages of the present invention will be apparent from the detailed description of the invention and from the claims.